The majority of life threatening ventricular arrhythmias occur in patients suffering from ischemic heart disease. Reperfusion (reoxygenation) of the ischemic heart tissue and administration of antiarrhythmic drugs, follow the case of myocardial infarctions. However the use of antiarrhythmic drugs to suppress arrhythmias and prevent sudden cardiac death has limited success (Woosley R. L. “Antiarrhythmic drugs” Annu. Rev. Pharmacol. Toxikol. 1991, 31, 427).
Accumulated evidence suggests that the injury sustained by the heart, following a case of acute myocardial ischemia occurs during reoxygenation. It is believed that the biochemical changes occurring during the ischemic period produce a burst of active oxygen species (AOS) when molecular oxygenation is reintroduced (McCord J. M. “Oxygen-derived free radicals in postischemic tissue injury” N. Engl. J. Med. 1985, 312, 159). These oxygen radicals include superoxide (*O2−) which is a precursor of several more toxic radicals such as hydroxyl radical (*OH). It is postulated that these free radicals react with the phospholipid components of myocardium. Such reactions affect the selective permeability of cell membranes and are related to the development of life threatening ventricular arrhythmias and/or fibrillation. Under normal conditions cells are protected from such reactions by various enzymes and by some small molecules which are normally involved in cellular redox reactions. However, these biochemical processes are inadequate during hypoxic conditions. Treatment with antioxidants such as α-tocopherol has been shown to reduce membrane related alterations resulting from ischemia and reperfusion (Massey K. D., Burton K. P. “α-Tocopherol attenuates myocardial membrane-related alterations resulting from ischemia and reperfusion” Am. J. Physiol. 1989, 256, H1192).
Accordingly, it would be advantageous to develop bifunctional agents which will act as antiarrhythmic antioxidants. These bifunctional drugs should preferentially segregate in the membrane and produce their antiarrhythmic effects while, at the same time, help in protecting the membrane lipids by scavenging free radicals.
Thus the pharmacophore backbone of structural analogs of vitamin E and key features responsible for the antiarrhythmic properties of class I or class III antiarrhythmics were combined in one molecular scaffold. Lipophilic features have been incorporated in order to achieve favorable partitioning in the myocardial membranes.
The molecular design also has taken into account all available information on structure activity relationships for optimal antiarrhythmic activity with minimal undesirable effects.